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HGG in Patients with LFS: Comparison
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Please note this is a comparison between Version 2 by Lindsay Dong and Version 3 by Lindsay Dong.

Li-Fraumeni syndrome (LFS) is a rare high-penetrance and autosomal-dominant pathological condition caused by the germline mutation of the TP53 gene, predisposing to the development of tumors from pediatric age. High-grade glioma (HGG) is a common tumor in children.

  • Li-Fraumeni syndrome
  • embryonal rhabdomyosarcoma
  • high-grade bithalamic glioma
  • NTRK genes

1. Introduction

Li-Fraumeni syndrome (LFS) predisposes to the early onset of a wide variety of cancers associated to a germ line mutation in the TP53 gene, located on the 17p13.1 chromosome. This mutation has a high-penetrance and an autosomal-dominant transmission pattern. The p53 protein encoded by the homologous gene plays a complex and important role in repairing DNA damage and preventing cellular oxidative stress, acting as a tumor suppressor factor. Therefore, mutations causing a loss of its function, as happens in LFS, predispose to the onset of tumors such as sarcomas, osteosarcomas, breast cancers and pheochromocytomas from childhood. Among brain tumors, the most frequently found are low-grade gliomas, medulloblastomas and choroid plexus carcinomas in pediatric age and high-grade gliomas (HGGs) in adulthood. Some patients develop multiple tumors from pediatric age.

2. High Grade Gliomas in Patients with Li-Fraumeni Syndrome

A total of six cases of pediatric patients with LFS and brain HGGs were identified (Table 1). Among these, four were described by Sloan and colleagues [1], who performed a comprehensive genomic characterization and studied the clinicopathologic features. García-Cárdenas et al. [2] reported a case of an Ecuadorian pediatric patient with anaplastic astrocytoma genetically characterized using a panel-based next-generation sequencing, whereas Zureick et al. [3] reported the case of a 14-year-old boy with LFS and a gigantocellular-type glioblastoma multiforme successfully treated with surgical resection, radiotherapy and Everolimus administration. In this case, target therapy was motivated by the results of whole exome and transcriptome sequencing revealing germline TP53 and somatic TSC2 mutations that emerged as markers of response to mTOR inhibitors [4].

Table 1. High grade gliomas in patients with Li-Fraumeni syndrome: reported cases in the literature.

Reference No. IDH Mutation Status Age and Sex Other Cancers Family History Brain Tumor Histology Location Follow Up
Sloan et al. [1] 1 Wildtype 4, Male None Negative Glioblastoma Thalamus 2 months
  2 Wildtype 6, Male None Negative Glioblastoma Cerebral hemisphere 12 months
  3 Wildtype 11, Male Osteosarcoma Brain cancer (aunt); ovarian cancer (grandmother); rhabdomyosarcoma (uncle) Anaplastic astrocytoma Cerebral hemisphere 8 months
  4 Wildtype 6, Male None Negative Glioblastoma Cerebral hemisphere 4 months
García-Cárdenas et al. [2] 5 n.e * 13, Female None Breast cancer (mother and maternal grandmother); brain cancer (two maternal uncles and two maternal cousins) Anaplastic astrocytoma Cerebral hemisphere 17 months
Zureick et al. [3] 6 n.a. ** 14, Male n.a. ** n.a. ** Glioblastoma Cerebral hemisphere 33 months
Our case 7 Wildtype 3, Male Rhabdomyosarcoma Ovarian cancer (great-grandmother); leukemia (cousin) Glioblastoma Thalamus bilateral 4 months
* n.e. not evaluated; ** n.a. not available.

Median age at tumor diagnosis was eight years. Among patients whose cancer history was available (five out of six), four had no previous history of other malignancies and one patient had previously been diagnosed with an osteosarcoma. Screening for tumor location disclosed five cases involving cerebral hemispheres and one involving thalamus. With regards to survival data, three patients with glioblastoma died and the other glioblastoma patient was still alive but with evidence of progressive disease after four months of follow up. Of the two patients diagnosed with anaplastic astrocytoma, one died after 17 months and the other one was alive with no evidence of progression at eight months follow up.

3. Conclusions

It is estimated that about 10% of children with central nervous system (CNS) tumors harbor an underlying cancer-predisposition syndrome [5][6][7][8], the most frequent being LFS, whose prevalence is 1:5000–20,000. The diagnosis of LFS is established in a proband meeting all three classic criteria and/or tested positive to TP53 germline mutation. Classic LFS criteria include: (1) a sarcoma diagnosed before age 45 years; (2) a first-degree relative with any cancer diagnosed before age 45 years; (3) a first- or second-degree relative with any cancer diagnosed before age 45 years or a sarcoma diagnosed at any age [9]. The “Chompret’s Revised Criteria” integrated the classic criteria as regards to the indication of testing for LFS [10].

In affected individuals, the risk of developing at least one tumor in lifetime is 75% among men and 93–100% among women. According to Olivier et al. [11] median age of onset of brain tumors in Li-Fraumeni syndrome is sixteen years and about 40% of affected children will develop a cancer by the age of 18 [12]. Pediatric CNS tumors in LFS represent the second most common cancer after adrenocortical carcinomas. Among brain tumors, the most frequent in pediatric age are low-grade gliomas, medulloblastomas and carcinomas of the choroid plexus, while adults have a higher incidence of HGG [5]. Thalamic HGG account for 13% of HGG in pediatric age and have a very unfavorable prognosis [13]. Our case is unique in several aspects: from an epidemiological point of view, to our knowledge there is no previous report of a bithalamic HGG in a pediatric patient with LFS. Despite patients with LFS being likely to develop a second malignancy before 18 years of age, there are no other reports in the literature of an embryonal rhabdomyosarcoma and an HGG in the same patient at such a young age.

In LFS the negative prognostic factor of somatic TP53 mutation, associated with a TP53 germline mutation, hallmark of the disease, seems confirmed by some initial evidences: Boyle et al. [14] studied the effect of RT in fibroblasts derived from non-LFS, LFS (mutant TP53) and LFS (wild-type TP53) patients and observed that >50% chromosomal aberrations were accumulated in fibroblasts with mutant TP53, significantly more than in fibroblasts of the other groups, after irradiation. Moreover, TP53 mutated gliomas in LFS seem to have a higher potential for progression toward higher grades compared to TP53 wild-type gliomas [15]. Mutation of TP53, as occurs in LFS, not only neutralizes the P53 protein’s normal tumor suppressive function, but may also disrupt cellular regulatory networks, thus enabling tumor cells to avoid genotoxic signals such as from gamma radiation, circumventing senescence and programmed cell death [16][17][18][19].

In case of LFS progression, ongoing studies are evaluating the therapeutic efficacy of Larotrectinib for those patients that, unlike our patient, have fusion-transcripts of the NTRK1 gene [20][21][22]. The NTRK1 gene encodes a protein-kinase located on the cell surface, in particular on sensory neurons, that phosphorylates specific loci of other proteins, thus modulating their activity in order to regulate cell growth and survival. Mutations of this gene, especially rearrangements with other genes with fusion-transcripts formation, are related to various types of cancer and tumor-predisposing syndromes. An analysis has therefore been carried out using NGS (Next Generation Sequencing) technique on the glioma cells of our patient, showing the presence of fusion-transcripts of the NTRK2 gene. However, considering that the biological role of NTRK2 gene is still unknown and no indication for Larotrectinib use has been registered yet in this rare cohort of patients [23], no further treatment was administered. Therefore, further research on NTRK genes is needed, in order to define more target therapies indications and strategies [24][25].

 

References

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